Abstract Personalized neoantigen cancer vaccines have been at the forefront of therapeutic vaccination. However, although these neoantigen vaccines do induce neoantigen-specific T cell responses, the clinical effects are limited. Logistical challenges, such as the time required for developing personalized neoantigen vaccines, also limit their clinical utility. We were recently intrigued by a case at Penn where one of our patients had a 7.6 cm melanoma tumor and experienced a complete response after receiving the COVID-19 vaccine alone, consistent with a recent report that cancer patients who received the SARS-CoV-2 vaccination had improved survival. Further studies identified abundant SARS-CoV-specific T cells present in both the draining lymph node (LN) and in the necrotic tumor bed. At the same time, our preliminary experiment in mice showed a similar phenomenon that the activation of tumor-irrelevant CAR T cells by vaccination reinvigorated the host’s tumor-specific immunity and regressed established solid tumors. Specifically, when we used our recently developed lipid polymer vaccine (Ma et al, Science, 2019; Cell, 2023; Grzywa et al, Nat BME, 2025) carrying a chemical ligand Fluorescein (FITC) to specifically stimulate adoptively transferred bystander FITC-targeting chimeric antigen receptor (CAR) T cells in vivo in the lymph node as a negative control, yet unexpectedly we observed distal tumor regression to a level that’s comparable to vaccine stimulation of tumor-specific CAR T in syngeneic mouse models of pancreatic cancer and melanoma. In both settings, tumor volume was reduced by70% within the first 72 hours, and this effect persisted for up to 2 weeks (with some cures of the melanoma). This marked antigen-independent tumor control is completely lost in Rag1-knockout (no endogenous T cells) and BatF3-knockout (deficient in antigen cross-presentation) recipient mice. FITC vaccine boosting of bystander FITC-CAR T induced a rapid and transient cytokine and chemokine release that distally remodels the tumor microenvironment. Notably, IFNg blockade completely abolished this tumor control. In the pancreatic cancer model, IFNg significantly upregulated PD-L1 expression in cancer cells. As a result, co-administration of anti-PD-L1 markedly extended long-term tumor control and animal survival. Collectively, these unexpected findings in both the melanoma patient and syngeneic mouse models of solid tumors suggested a previously unappreciated anti-tumor bystander effect associated with vaccine-mediated T cell activation. Citation Format: Leyuan Ma, Tomasz Grzywa, Ryan Tannir, Gregory L. Beatty, Alexander Huang. Vaccine stimulation of bystander t cells in the lymph node unexpectedly promotes tumor-specific host immunity to regress solid tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1350.
Ma et al. (Fri,) studied this question.